A major goal of HIV-1 research is to develop vaccines that induce high titers of virus neutralizing antibodies (NAb) with the goal of preventing infectio. However, this goal is proving difficult to achieve. In the absence of NAb, there is a short window of opportunity where vaccine-induced non-neutralizing antibodies might prevent widespread HIV-1 infection and deregulation of CD4+ T-cells. It is our overall goal therefore to develop a potentially new class of HIV vaccines that rely on a broad range of antibody effector functions capable of clearing both free and cell-associated virus. Specifically, we hypothesize that a matrix (M) gene- deleted rabies virus-based vaccine expressing HIV antigens will induce antibodies with potent Fc-mediated non-neutralizing antibody effector functions and may hold promise as effective HIV-1 vaccines. Our hypothesis is based on several factors: 1) non-neutralizing antibodies mediate and regulate a broad range of anti-viral effector functions that effectively clear both free and cell-associated virus particles, 2) a growing body of evidence supports a beneficial role for non-neutralizing antibodies in the control of SIV infections in non-human primates and in the protection against pathogenic SIV or SHIV challenge after vaccination, and 3) M gene- deleted RV-based vectors induce highly Th1-type polarized antibody responses, which are highly effective at inducing antibodies with non-neutralizing effector functions, such as antibody-dependent cellular cytoxocity (ADCC) and antibody dependent cellular virus inhibition (ADCVI). We believe we can exploit this feature of RV- M to further develop it as an HIV-1 vaccine capable of conferring protection mediated by non-neutralizing antibodies. This exploratory grant is the first phase of a multi-phased project aimed at studying RV-M as an HIV vaccine vector expressing HIV (or SIV) antigens. Therefore, the goal of this exploratory grant is to show that RV-DM expressing SIV Env induces potent Fc-mediated antibody effector functions in mice and that it has the potential for additional (future) studies in mice and non-human primates. Two Aims are proposed to achieve these goals. Aim I is directed towards constructing, recovering, and characterizing novel M gene-deleted RV-based vaccines expressing SIV Envelope. Aim II is directed towards confirming these new vaccine vectors induce non-neutralizing antibodies with broadly acting Fc-mediated effector functions, including ADCC and ADCVI, which have been shown to improve the outcome of vaccination in SIV or SHIV models of protection. The experiments described in this proposal will identify the efficacy of a novel vaccine vector with the potential of inducing potent non-neutralizing antibodies that might help to clear free and cell-associated virus. Once this is established, we will propose additional studies to advance the testing of the vaccines in non- human primates. PUBLIC HEALTH RELEVANCE: Over the past 25 years, over 1,700 reports have been published describing the role of neutralizing antibodies in HIV-1 infection; however, the development of effective antibody-based HIV-1 vaccines has not been successful. This highlights the need for the development of vaccination strategies capable of eliciting non- neutralizing antibodies with the capacity of clearing both free and cell associated virus, which play key roles in viral clearance during and after infection. In addition, it is important to move previously untested but promising vaccine vectors into the pipeline of potential HIV-1 vaccines, considering the difficulty in generating an effective HIV-1 vaccine to date. This exploratory grant will identify a vaccination strategy that promotes the development of antibodies with effective non-neutralizing functions.